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Table of Contents    
Year : 2019  |  Volume : 67  |  Issue : 4  |  Page : 1100-1106

Malignant Transformation of Pediatric Low-grade Gliomas: Report of Two Cases and Review of a Rare Pathological Phenomenon

1 Department of Neurosurgery, Sri Sathya Sai Institute of Higher Medical Sciences, Bengaluru, Karnataka, India
2 Department of Pathology, Sri Sathya Sai Institute of Higher Medical Sciences, Bengaluru, Karnataka, India

Date of Web Publication10-Sep-2019

Correspondence Address:
Dr. Sumit Thakar
Department of Neurosurgery, Sri Sathya Sai Institute of Higher Medical Sciences, Bengaluru - 560 066, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.266259

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 » Abstract 

Low-grade gliomas (LGGs) are the commonest benign central nervous system (CNS) tumors seen in children. Unlike LGGs in adults, pediatric LGGs rarely undergo malignant transformation. The incidence of malignant transformation of LGGs in the pediatric population has been reported to be up to 10%. Of these, a few patients have demonstrated this phenomenon even without adjuvant radiation therapy. We report two such unusual cases. A 7-year-old girl presented with a left temporal lesion that was operated upon and was reported as pilocytic astrocytoma (WHO grade I). She presented with a malignant transformation of the tumour 8 years later. The second case was a 10-year-old boy, who had a left frontoparietal ganglioglioma (WHO grade I) that demonstrated malignant transformation to an anaplastic ganglioglioma (WHO grade III) 10 months after the initial surgery. Multiple studies have thrown light on the molecular genetics behind malignant transformation of LGGs in children. These genetic changes can perhaps serve as targets for potential future therapeutic interventions. It is important that patients with LGGs at risk of malignant transformation must be identified early so that a more aggressive treatment strategy can be adopted.

Keywords: Anaplastic ganglioglioma, anaplastic pilocytic astrocytoma, ganglioglioma, malignant transformation, pediatric low-grade glioma, pilocytic astrocytoma
Key Message: Malignant transformation of pediatric LGGs is very unusual. It is important to stratify patients at risk of developing this so that they can be adequately and aggressively treated.

How to cite this article:
Avinash K S, Thakar S, Aryan S, Ghosal N, Hegde AS. Malignant Transformation of Pediatric Low-grade Gliomas: Report of Two Cases and Review of a Rare Pathological Phenomenon. Neurol India 2019;67:1100-6

How to cite this URL:
Avinash K S, Thakar S, Aryan S, Ghosal N, Hegde AS. Malignant Transformation of Pediatric Low-grade Gliomas: Report of Two Cases and Review of a Rare Pathological Phenomenon. Neurol India [serial online] 2019 [cited 2021 Jan 23];67:1100-6. Available from:

Low-grade gliomas (LGGs) are the most common central nervous system (CNS) neoplasms in children. The term “pediatric LGGs (PLGGs)” encompasses a heterogeneous set of tumors, which histologically conforms to WHO grades I or II and accounts for 30–50% of all CNS neoplasms.[8],[20] A majority of the PLGGs display an indolent clinical behavior. Spontaneous malignant transformation of such tumors is a phenomenon that has been rarely reported.[2],[4],[6],[9],[12],[13],[16]

 » Case Reports Top

Case 1

A 7-year-old girl presented with a history of seizures since 3 months. She had no focal deficits but had papilledema. Magnetic resonance imaging (MRI) of the brain [Figure 1] showed a 6.9 cm × 5.3 cm × 5 cm sized well-defined lesion in the left temporal lobe extending into the thalamus and enhancing heterogeneously with contrast. She underwent left temporal craniotomy and partial excision of the tumor. This was followed by re-exploration and subtotal excision of the residual tumour 4 months later. The postoperative MRI showed residual tumor in the left thalamus. Microscopically [Figure 2], the tumor tissue comprised piloid cells with eosinophilic granular bodies and few Rosenthal fibers. In addition, there were foci showing pleomorphic cells with giant cells and microvascular proliferation. Mitosis and necrosis were not seen. These features were consistent with the diagnosis of pilocytic astrocytoma (WHO grade I). A follow-up MRI 1 year later showed no growth of the residual tumor. Subsequently, the child presented 8 years later with a 15-day history of headaches. Imaging [Figure 3] showed that the tumor had grown to involve the left temporal and parietal lobes, and demonstrated ependymal and subarachnoid spread. She underwent re-exploration and tumor decompression. The histopathology of this tumor showed [Figure 4] areas with marked cellularity, nuclear pleomorphism, brisk mitotic activity, microvascular proliferation, and focal necrosis. These tumor cells were strongly positive for GFAP and demonstrated increased MIB-1 labeling index of 8–10%. These features were consistent with the diagnosis of a malignant transformation of pilocytic astrocytoma (anaplastic pilocytic astrocytoma; WHO grade III). She was referred to an oncologist for adjuvant therapy and was lost to follow up thereafter.
Figure 1: MRI showing a well-defined lesion in the left temporal lobe extending into the posterior thalamus: (a) T1-weighted sequence, (b) T2-weighted sequence, (c) post-gadolinium T1-weighted sequence

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Figure 2: Paraffin section showing (a) piloid areas with many (b) eosinophilic granular bodies (arrow) and (c) Rosenthal fibers. [Hematoxylin and eosin: (a and c) ×100; (b) ×400]

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Figure 3: MRI showing a recurrent tumor in the left temporo-parietal region: (a) T2-weighted sequence, (b and c) post-gadolinium T1-weighted sequences showing: (b) extension into the ventricle with ependymal enhancement, and (c) subarachnoid spread of the tumor

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Figure 4: Paraffin section showing (a) typical pilocytic area (straight arrow) juxtaposed with anaplastic area (curved arrow), with (b) nuclear hyperchromasia, brisk mitotic activity (straight arrow), (c) foci of necrosis, and (d) immunopositivity for GFAP in tumor cells. [Hematoxylin and eosin (a and c) ×100; (b) ×400] [Avidin Biotin Complex Immunoperoxidase (d) ×100]

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Case 2

A 10-year-old boy presented with a history of seizures for 5 years. On examination, he had a right upper limb pronator drift. His MRI brain [Figure 5] showed a 7.5 cm × 9.8 cm × 6.3 cm solid-cystic lesion in the left frontoparietal region. He underwent left frontoparietal craniotomy and excision of the lesion. Postoperative MRI showed the complete excision the tumor. Paraffin-embedded sections [Figure 6] showed spindle-shaped astrocytes with piloid and Rosenthal fibers and eosinophil granular bodies. Nuclear atypia was seen with multinucleated giant cells and admixed dysmorphic ganglion cells. The glial component was positive for GFAP; occasional ganglion cells were positive for synaptophysin. The histology was consistent with ganglioglioma (WHO grade I).
Figure 5: MRI showing a solid-cystic lesion in the left frontoparietal region. The mass appeared isointense on (a) T1- and (b) T2-weighted sequences with (c) heterogeneous contrast enhancement

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Figure 6: Paraffin section showing (a) many eosinophilic granular bodies (straight arrow) with focal cellular pleomorphism, (b) tumor cells arranged in linear pattern focally, and (c and d) occasional neuronal cell component (curved arrow). Tumor cells immunopositive for GFAP (B-inset). [Hematoxylin and eosin: (a and b) ×100; (c and d) ×400] [b, Inset: Avidin Biotin Complex Immunoperoxidase ×400]

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He presented with progressive weakness of the right upper and lower limbs 10 months later. Imaging showed recurrence of the tumor [Figure 7] within the previous cavity with perilesional edema. He underwent re-exploration and complete excision of the tumor. Microscopically [Figure 8], there were foci of necrosis and high mitotic activity (15-16/10 HPF). The tumor was rich in reticulin in areas other than the ones with glial differentiation. On immunohistochemistry, tumor cells were strongly positive for vimentin, GFAP, and S-100 protein. CD34 positivity was seen in non-glioma tumor cells; the tumor cells were negative for epithelial membrane antigen and smooth muscle actin. Though the morphological features were akin to those of a gliosarcoma, the overall diagnosis based on the WHO 2016 classification was consistent with that of an anaplastic ganglioglioma (WHO grade III). He underwent radiotherapy (60 gray in 30 fractions) and chemotherapy with vincristine, carboplatin, and etoposide. He remained asymptomatic for the next 30 months; however, an MRI done thereafter showed a small enhancing nodule in the left internal capsule. He was referred for further chemotherapy.
Figure 7: MRI showing recurrence of tumor in the left fronto-parietal region: (a) T2-weighted sequence and (b) and (c) post-gadolinium T1-weighted sequences

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Figure 8: Paraffin section showing (a) fascicular arrangement of spindle cells with (b) brisk mitotic activity (curved arrow), (c) few cells immunopositive for GFAP, and (d) other cells immunopositive for CD34. [Hematoxyllin and eosin: (a) ×100, (b) ×400] [Avidin Biotin Complex Immunoperoxidase: (c) ×100; (d) ×400]

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 » Discussion Top

Unlike adult LGGs which show a high propensity to progress to high-grade gliomas, PLGGs rarely undergo malignant transformation, with a maximum reported incidence of 10%.[4] From a Pubmed search, we identified a total of 44 previously reported biopsy-proven cases of PLGGs that had undergone malignant transformation.[1],[2],[3],[4],[5],[6],[7],[9],[10],[12],[13],[14],[16],[17],[19],[22],[23],[25],[26],[27],[28],[29],[30],[31],[32] This included tumors that demonstrated malignant transformation spontaneously or following radiation therapy. The details of these cases including patient and tumour characteristics are listed in [Table 1]. In these compiled cases, malignant transformation occurred at varying periods, from less than a year to 52 years after the initial treatment. The cerebellum was the most common site of primary lesion, followed by the thalamus. Of the 44 reported cases, 26 had received radiotherapy after the primary treatment.[1],[3],[4],[5],[7],[10],[13],[17],[22],[23],[25],[26],[27],[28],[29],[30],[31] Of the 18 patients who demonstrated spontaneous transformation of tumor to high-grade lesions,[2],[4],[6],[9],[12],[14],[17] 6 had received chemotherapy after the primary surgery.
Table 1: Review of pediatric LGGs that underwent malignant transformation

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Significant advances have taken place in recent years in understanding the molecular characteristics of gliomas in relation to their clinical behavior and recurrence patterns. A study on the Indian population with adult LGGs has identified gemistocytic morphology, p53 overexpression and microvascular density count of more than 20 to predict early recurrence and aggressive tumor behavior.[21] Differential changes in molecular pathways in adult and pediatric populations have been reported from another large Indian study that focused on the frequency of 1p/19q codeletion in oligodendroglial tumors.[18] With respect to PLGGs, some studies have demonstrated alterations causing activation of the MAPK/ERK pathway,[11] with the most common one being the oncogen BRAF. A molecular analysis in pediatric patients with malignant transformation of LGGs [4] reported that overall, while 71% of PLGGs had abnormalities of the retinoblastoma tumor-suppressor pathway (CDKN2A and/or RB1 deletion), 90% of PLGGs after malignant transformation demonstrated the same mutations. PTEN deletion was observed after malignant transformation in more than half of the patients in the same study. An integrative genetic and molecular analysis of childhood sHGGs [24] revealed that no sHGG harbored the 7q34 duplication, which is indicative of BRAFKIAA549 gene fusion, and there was a high proportion of p53 immunopositive sHGG (72%) versus PLGG (27%).

In the largest study till date, Mistry et al.[15] reported an analysis of molecular characteristics of 26 children with PLGGs with malignant transformation. Patient-matched low- and high-grade samples in this study revealed that BRAF mutations identified in the sHGGs were also identified in 100% of the corresponding PLGGs and that 80% of sHGG CDKN2A deletions were also identified in the corresponding PLGGs. It was also demonstrated that BRAF V600E and CDKN2A deletions were significantly enriched in PLGGs that transformed. These were present in 44% and 71% of PLGGs that transformed compared with 6% and 20% respectively of PLGGs that did not transform PLGGs that later transformed also harbored overexpression of p53 or CDKN2A deletions.

PLGGs have been stratified based on genetic alterations into different risk groups.[15] Tumors that have the BRAF fusion but lack genetic alterations have a very low risk for transformation. Those harboring the BRAF V600E mutations and alterations in CDKN2A or TP53 have a higher risk for transformation. PLGGs originating with cancer predisposition syndromes associated with HGG eventually transform, and midline PLGGs harboring H3.3 K27M mutations behave as primary HGGs. In the future, the inclusion of the genetic tests for these mutations at primary diagnosis may enable early detection of high-risk patients. Therapy targeted at specific genetic endpoints, in addition to aggressive surgical resection may help mitigate the malignant transformation event in PLGGs. It would have been worthwhile ascertaining the molecular features of the primary and secondary tumors in our patients; however, the cytogenetic analysis facility for the same is not available at our institute.

 » Conclusion Top

Although LGGs in children typically demonstrate an indolent clinical course, they can rarely undergo malignant transformation, with these secondary high-grade gliomas demonstrating a poor prognosis. We report two such unusual cases that demonstrated a spontaneous malignant transformation of LGGs. Understanding the molecular characteristics of these tumors will help adopt an aggressive surgical strategy, frequent surveillance, and, in the future, targeted molecular therapy.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.

 » References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]

  [Table 1]


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